Our current and future research utilizes antibody technology for the generation of a large nave human Fab library in a newly designed phage display vector. We anticipate that this phage display library will become an important source for the generation of human monoclonal antibodies (mAbs) to a number of targets with relevance for hematologic malignancies. In FY05, we selected human mAb KYK-1 to human NKG2D from this library. NKG2D is expressed on NK cells which mediate the perhaps most important activity mechanism of antibodies, i.e. antibody-dependent cellular cytotoxicity (ADCC). We are currently evaluating KYK-1 (i) as diagnostic and therapeutic targeting device for NK-cell lymphoma and leukemia and (ii) for the generation of bispecific antibodies designed to recruit NKG2D+ NK cells and NKG2D+ CD8+ T cells to the tumor site. For the latter project we are building an interface of antibody technology and synthetic peptide and peptidomimetic chemistry. Specifically, we are combining intein technology and click chemistry to explore new routes to bispecific antibodies.Complementing our efforts for generating human monoclonal antibodies, we are continuing the mining of rabbit antibody repertoires by phage display. In particular, we have generated rabbit monoclonal antibodies selective for all three members of the Nogo receptor (NgR) family. NgR family members are cell surface proteins involved in the development, plasticity, and regeneration of the central nervous system. However, we have found recently that mRNAs of NgR family members are expressed also by peripheral blood mononuclear cells (PBMCs). Our rabbit monoclonal antibodies will allow us to detect and define NgR family member expression on the surface of normal and malignant lymphocytes with a particular emphasis on T-cell and B-cell lymphoma and leukemia.